Prognostic Significance of Chromosome Aberrations in High-Grade Soft Tissue Sarcomas (original) (raw)
Cancer research, 2002
Cytogenetic analysis has not only provided important information on the pathogenesis of soft tissue tumors but, by disclosing distinct chromosomal rearrangements in different histopathological entities, has also come to serve as a valuable diagnostic tool. Little is known as yet about the potential prognostic impact of cytogenetic features detected in these tumors. A total of 239 benign and 221 malignant soft tissue tumors with clonal chromosome aberrations were subdivided according to general karyotypic features, such as degree of complexity and ploidy level, and rearrangements of specific chromosomal regions. The cytogenetic variables were analyzed regarding clinical outcome, using time to metastasis as the end point. Selected variables were then compared with established clinicopathological predictors of metastasis development. When the entire material was considered, 167 of 268 investigated cytogenetic variables were associated with clinical outcome. Focusing on the subset of 15...
International Journal of Cancer, 1997
The most important prognostic factor in soft tissue sarcomas (STS) is tumor grade. Since most grading methods are subject to the interpretation of the individual pathologist, there is a need for objective criteria such as DNA ploidy and karyotype, which are of prognostic value in several types of malignancy. We have analyzed the relationships among tumor grade, DNA ploidy, cytogenetic abnormalities and the clinical outcome of 44 previously untreated patients with 12 different histological types of primary STS. The tumors were graded according to the method of Coindre, which resulted in 9 grade I (20%), 18 grade II (41%) and 17 grade III (39%) STS. DNA flow cytometry and chromosomal analysis were performed using standard techniques. After a median follow-up time of 39 (range, 2-124) months, Kaplan-Meier survival analysis was performed. Significant differences in 5-year overall survival were found between patients with grade I or II and grade III STS (p F 0.05). Seventeen STS were aneuploid and 26 were euploid. In 21 of 39 successfully cultured STS an abnormal karyotype was found. There were no significant differences in survival in relation to DNA ploidy or the presence of chromosomal abnormalities. Our results show that grading had higher prognostic value than DNA ploidy or the presence of cytogenetic abnormalities in this heterogeneous group of STS. Int.
The role of cytogenetics and molecular diagnostics in the diagnosis of soft-tissue tumors
Modern Pathology, 2014
Soft-tissue sarcomas are rare, comprising o1% of all cancer diagnoses. Yet the diversity of histological subtypes is impressive with 4100 benign and malignant soft-tissue tumor entities defined. Not infrequently, these neoplasms exhibit overlapping clinicopathologic features posing significant challenges in rendering a definitive diagnosis and optimal therapy. Advances in cytogenetic and molecular science have led to the discovery of genetic events in softtissue tumors that have not only enriched our understanding of the underlying biology of these neoplasms but have also proven to be powerful diagnostic adjuncts and/or indicators of molecular targeted therapy. In particular, many soft-tissue tumors are characterized by recurrent chromosomal rearrangements that produce specific gene fusions. For pathologists, identification of these fusions as well as other characteristic mutational alterations aids in precise subclassification. This review will address known recurrent or tumor-specific genetic events in soft-tissue tumors and discuss the molecular approaches commonly used in clinical practice to identify them. Emphasis is placed on the role of molecular pathology in the management of soft-tissue tumors. Familiarity with these genetic events provides important ancillary testing for pathologists to include in their diagnostic armamentarium.
Curent concepts in pathology of soft tissue sarcoma
Indian journal of surgical oncology, 2011
Soft tissue sarcomas (STS) constitute a heterogeneous category of soft tissue neoplasia composed mostly of uncommon tumors of diverse histology, different biology and varied outcomes. Substantial developments in immunohistochemistry (IHC), cytogenetics and molecular genetics of STS have caused a significant change in the classification and diagnosis of these tumors with a direct implication for clinical management and prognosis. In this review we discuss newer developments impacting diagnosis and prediction.
Increased risk of malignancies in a population-based study of 818 soft-tissue sarcoma patients
British journal of cancer, 2006
Soft-tissue sarcomas (STS) have been associated with various rare cancer syndromes and occur at increased frequencies in survivors of childhood cancer. Also adult patients with STS have been suggested to be at an increased risk of additional malignancies. After exclusion of syndrome-associated and radiation-induced sarcomas, we studied multiple primary malignancies in a population-based cohort of 818 patients with primary STS of the extremities and the trunk wall. In total, 203 other malignancies developed in 164 (20%) patients median 10 (0-32) years before and median 4 (0-35) years after the sarcoma diagnosis. Standardised morbidity ratios (SMRs) were determined for primary malignancies following a STS. Hereby individuals who had developed a STS were identified to be at increased risk of second primary malignancies (SMR for all malignant tumours=1.3; 95% CI=1.0-1.5; P=0.02) with STS being the only specific tumour type that occurred at an increased risk (SMR=17.6; 95% CI=8.1-33.5; P...
Identification of low-risk tumours in histological high-grade soft tissue sarcomas
European Journal of Cancer, 2007
Growth pattern Size Necrosis A B S T R A C T In more than one-third of patients with a histological high-grade malignant soft tissue sarcoma metastasis develops despite local control of the primary tumour. Hence, adjuvant chemotherapy is increasingly used for these relatively chemoresistant tumours which requires improved prognostication to exclude low-risk patients from overtreatment. We assessed the value of stepwise prognostication in a series of 434 histological high-grade STS of the extremity and trunk wall. Vascular invasion was used as the first discriminator whereafter the risk factors tumour necrosis, size (>8 cm) and infiltrating growth pattern were used to discriminate high-and low-risk tumours. We identified a high-risk group with a cumulative incidence of metastasis >0.4 at 5 years, and a low-risk group, comprising half of the tumours, with a cumulative incidence of metastasis <0.15. The model was validated in an independent material of 175 patients. This model improved prognostication in STS and is of value for identifying patients who probably should not receive adjuvant chemotherapy.
A retrospective statistical analysis of high-grade soft tissue sarcomas
Medical Oncology, 2011
Soft-tissue sarcomas have a mortality rate ranging from 40-60% for high-grade lesions. Prior identified risk factors for post-surgical mortality include tumor size, lesion histology, and margin status at resection. A better understanding of prognostic factors is needed to guide patient counseling and treatment. Data were collected from 129 patients surgically treated for high-grade extremity soft tissue sarcomas during 2002-2010. The primary endpoint was death related to high-grade soft tissue sarcoma. Thirteen variables were investigated: age, gender, race, tumor size, margin status, location, estimated blood loss, operative blood transfusions, pre-operative metastatic disease, pre-operative radiation, post-operative radiation, pre-operative chemotherapy, and post-operative chemotherapy. A Cox Survival Analysis model was created to determine the best predictors of survival time. Tumor size and the presence of pre-surgical metastasis were statistically significant predictors of overall survival. Patients with a tumor greater than 8 cm in any cross section had a 3.15 times greater chance of death. Presence of pre-surgical metastasis carried a 3.47 greater chance of death. The remaining variables did not predict patient outcomes in a statistically significant manner. The hazard ratios calculated add new data and can be used to more effectively guide patients in prognosis and treatment regimens.
Cancer, 1984
A multidisciplinary study of 163 patients treated at the NCI for soft tissue sarcomas allowed the correlation of a number of histologic features (histologic type, mitosis, necrosis, pleomorphism, cellularity, and matrix) of the primary lesion to time to recurrence and overall survival of the patients. The results of the stratified analyses show that necrosis is the single best histopathologic parameter to predict the time to recurrence (P = 0.025) and the overall survival of the patients ( P = 0.002). Necrosis in the primary lesion is also of value in predicting survival after the first recurrence has taken place (P = 0.001). The value of necrosis in the primary lesions predicting the clinical course after recurrence appears to be independent of age, sex, location, and size of the tumor. The authors propose a grading system based on histologic typing and histologic parameters to identify a group of lesions with minimal metastatic potential (Grade l), and on the use of necrosis to distinguish between aggressive lesions with good patient survival (Grade 2) and aggressive lesions with poor patient survival (Grade 3).
The Clinical Relevance of Molecular Genetics in Soft Tissue Sarcomas
Advances in Anatomic Pathology, 2010
Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors including more than a hundred different entities attending to histologic patterns. Research into the molecular aspects of sarcomas has increased greatly in the last few years. This enormous amount of knowledge has allowed, for instance, to refine the classification of sarcomas, improve the diagnosis, and increase the number of therapeutical targets available, most of them under preclinical evaluation. However, other important key issues, such as sarcomagenesis and the cell of origin of sarcomas, remain unresolved. From a molecular point of view, these neoplasias are grouped into 2 main types: (a) sarcomas showing relatively simple karyotypes and translocations, which originate gene fusions (eg, EWS-FLI1 in Ewing sarcoma) or point mutations (eg, c-kit in the gastrointestinal tumors) and (b) sarcomas showing unspecific gene alterations, very complex karyotypes, and no translocations. The discovery of the early mechanisms involved in the genesis of sarcomas, the more relevant signaling pathways, and the development of genetically engineered mouse models could also provide a new individualized therapeutic strategy against these tumors. This review describes the clinical application of some of the molecular alterations found in sarcomas, some advances in the field of sarcomagenesis, and the development of animal models.
Cytogenetic intratumor heterogeneity in soft tissue tumors
Cancer Genetics and Cytogenetics, 1994
Multiple (two to seven) samples, obtained from the same surgical specimen or at different occasions, were analyzed in 54 benign and malignant soft tissue tumors, to investigate cytogenetic clonal evolution. In 28 tumors only normal karyotypes were found. Ten tumors had abnormal karyotypes, but were noninformative, most often due to a high level of karyotypic complexity or great cell-to-cell variation. Sixteen tumors were informative: four (leiomyosarcoma, liposarcoma, malignant Schwannoma, and a benign mesenchymal tumor, probably leiomyoma) had identical karyotypes in different samples, whereas the remaining 12 tumors (seven malignant fibrous histiocy~omas /MFH], two leiomyosarcomas, two liposarcomas, and one synovial sarcoma) displayed intersample heterogeneity. Also, intrasample heterogeneity was detected; more than one clone was found in 21 of 73 samples with aberrations from 26 tumors. The different clones were related in all cases except two. In seven cases, samples from different occasions were studied, and clonal evolution could be evidenced in five of them, whereas in two cases the karyotypes remained unchanged. The results indicate that the acquisition of ring chromosomes is an early event in the development of MFH and possibly also pleomorphic liposarcoma. The findings, together with previous data, also indicate that rearrangements of 19p13 are late events in the progression of pleomorphic sarcomas. The overall conclusion from this study is that cytogenetic heterogeneity is common in soft tissue tumors, and that this might influence the evaluation of cytogenetic and molecular genetic findings.
Sarcoma, 2008
Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult. Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype. Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS. Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications.
Correlation between Clinicopathological Features and Karyotype in Spindle Cell Sarcomas
The American Journal of Pathology, 1999
Soft-tissue tumors have proved to be a fruitful area for the identification of reproducible cytogenetic aberrations , especially among pediatric round-cell sarcomas and lipomatous tumors. Thus far , however, data regarding sarcomas of monomorphic spindle cell type have been limited and somewhat disappointing, with the notable exception of synovial sarcoma. As part of an ongoing international collaborative study, 130 karyotyped spindle-cell sarcomas were reviewed and classified histologically , without knowledge of the clinical and karyotypic data , with the aim of identifying objective correlations between morphology, karyotype , and clinical parameters. Clonal chromosomal abnormalities were identified in 82 cases studied (63%) , but only in the group of synovial sarcomas was there clear correlation between the cytogenetic findings , in the form of a consistent t(X;18)(p11;q11), and morphology. Among leiomyosarcomas (41 cases) and malignant peripheral nerve sheath tumors (MPNSTs; 27 cases) as well as in individual examples of rarer entities , there was a general tendency for karyotypic complexity associated with frequent loss or rearrangement of chromosome arms 1p , 10p, 11q, 12q , 17p , and 22q. Rearrangements of 17q (the region of the NF1 gene) were seen in 9/27 (33%) of MPNSTs. Among nine cases of solitary fibrous tumor (in which previous cytogenetic data are very limited) no consistent aberrations were identified. We conclude that, with the exception of synovial sarcoma , most spindle-cell sarcomas share with pleomorphic sarcomas the tendency for karyotypic complexity. There was no indication (in most of these lesions) that detectable cytogenetic aberrations could either facilitate their diagnosis or help to determine prognosis.
The Management of Adult Soft Tissue Sarcomas
American Journal of Clinical Oncology, 2009
Soft tissue sarcomas account for some 1% of adult cancers with an incidence of 37 cases per million person years [1]. Approximately 1200 new cases are reported each year in the UK. They are relatively more common in children (6%-7%) because of the reduced number of carcinomas in this group. In the majority of cases there is no clear aetiology. However, there are well established associations with genetically linked disorders such as von Recklinghausen's neurofibromatosis, tuberous sclerosis and the basal cell naevus and Li Fraumeni syndromes. Following a latent period of 5-25 years, a small proportion (<1%) of adults exposed to therapeutic doses of ionizing radiation develop sarcomas. This is more common in children who have received both radiotherapy and chemotherapy (18%). Patients often give a history of trauma but it is not clear whether this is causative or coincidental. Dioxin in the form of herbicide or defoliant (Agent Orange) has been implicated in causing an increased incidence of soft tissue sarcoma [2]. However, this association is not proven [3]. Genetics Many soft tissue tumours have consistent chromosome rearrangements. Chromosome translocations are the commonest type (Table 1). For example the translocation t(X;18)(p11.2;q11.2) is specific for synovial sarcoma and is seen in about 80% of patients. Structural alterations of the retinoblastoma locus are seen in some osteosarcomas and soft tissue sarcomas and may explain the association between familial retinoblastoma and these conditions. However, the division of turnouts into subgroups based on cytogenetic characteristics does not always correlate with histological subtype. Cytogenetics is an important area of future research in sarcomas and has already been of proven clinical benefit in the management of patients referred to this unit.
Lessons from genetic profiling in soft tissue sarcomas
Acta Orthopaedica, 2004
Soft tissue sarcomas represent a hetero- geneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are
Prognostication of Soft Tissue Sarcomas
Journal of Evidence Based Medicine and Healthcare
BACKGROUND Soft tissue sarcomas (STS) account for less than 1% of all malignant tumours but present a significant diagnostic and therapeutic challenge since there are more than 50 histological subtypes. 1 The clinical course of a sarcoma cannot be predicted by histologic typing alone but must be accompanied by grading and staging. Sarcomas with high metastatic potential can be picked out by histologic grading which is a cheap and simple method. One widely used and most reproducible grading system is French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) based on a score obtained by evaluating tumour differentiation, mitotic rate and amount of tumour necrosis. 2 Histologic grading is the mainstay in predicting prognosis of STS especially in centres where facilities for more sophisticated methods are not available. Hence this study was undertaken to assess the effectiveness of the FNCLCC grading system in the prognostication of STS in our patient population. Aims and Objectives 1. To grade soft tissue sarcomas according to the FNCLCC system. 2. To study the association between grade and survival of soft tissue sarcomas in the patient population.
Molecular classification of soft tissue sarcomas and its clinical applications
International journal of clinical and experimental pathology, 2010
Sarcomas are a heterogeneous group of tumors that are traditionally classified according to the morphology and type of tissue that they resemble, such as rhabdomyosarcoma, which resembles skeletal muscle. However, the cell of origin is unclear in numerous sarcomas. Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas. Molecular classification based on the genetic alteration divides sarcomas into two main categories: (i) sarcomas with specific genetic alterations; which can further be subclassified based on a) reciprocal translocations resulting in oncogenic fusion transcripts (e.g. EWSR1-FLI1 in Ewing sarcoma) and b) specific oncogenic mutations (e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specif...
International Journal of Cancer, 1984
The pathological features of 155 adult patients with soft-tissue sarcomas were studied retrospectively, in an attempt to set up a grading system for these tumors. As the first step, seven histological criteria (tumor differentiation, cellularity, importance of nuclear atypia, presence of malignant giant cells, mitosis count, pattern of tumor necrosis and presence of vascular emboli) were evaluated in a monofactorial analysis. Five of these (tumor differentiation, cellularity, mitosis count, tumor necrosis, and vascular emboli) were correlated with the advent of metastases and with survival. A multivariate analysis, using a Cox model, selected a minimal set of three factors (tumor differentiation, mitosis count, and tumor necrosis) the combination of which was necessary and sufficient to retain all the prognostic information. A grading system was elaborated, which turned out to be correlated with the advent of metastasis and with patients' survival. A second multivariate analysis introducing clinical prognostic features showed that the histological grade was the most important prognostic factor for soft-tissue sarcomas. Thus, this grading system appears to be highly interesting because of its prognostic value and the facility of its elaboration. However, its reproducibility should be tested.